Substituted amidinobenzene derivatives and medicinal compositions thereof

ABSTRACT

A substituted-amidinobenzene derivative of the following general formula (I) or a salt thereof, and a pharmaceutical composition comprising said derivative or a salt thereof and a pharmaceutically acceptable carrier. ##STR1## (the symbols in the above formula have the following meanings: R 1  : a group which can be converted into an amidino group in vivo; 
     R 2  and R 3  : the same or different and each represents a carboxyl group or a group which can be converted into a carboxyl group in vivo; 
     X 1  and X 2  : the same or different and each represents a lower alkylene group; 
     m: 0, 1 or 2; 
     n: 0 or 1, provided that n=1 when m=0. 
     They have GPIIb/IIIa receptor antagonizing activity and are useful as medicines for ameliorating ischemic cardiac disorders, adminicula in cardiosurgery operations or in vascular surgery operations, medicines for ameliorating cerebrovascular disorders, And medicines for ameliorating peripheral artery disorders. In addition, they are useful as a prodrug excellent in peroral absorbability and sustainment of the effect.

TECHNICAL FIELD

The present invention relates to novel substituted-amidinobenzenederivatives and their salts which are useful as medicines, especially asGPIIb/IIIa antagonists.

BACKGROUND ART

For a long period of time after the finding by Donne in 1842 (see C.R.Acad. Sci. (Paris), 14, 336-368, 1842); blood platelets have beenconsidered as the component in blood which is necessary for hemostasis.At present, it has been clarified that blood platelets not only play theprincipal part in the hemostatic mechanism of blood but also aremulti-functional as participating in the creation of arteriosclerosis,cardiovascular system disorders including thrombotic disorders, cancermetastases, inflammations, rejections after transplants, and alsoimmunoreactions, etc., which are clinically important. The thromboticdisorders and ischemic disorders are therapeutically treated byrestoring the circulation of the blood by the application of medicinesor by physical means. However, a clinically problematic phenomena hasbeen found recently that, after the restoration of the bloodcirculation, the activation, the adhesion and the aggregation of bloodplatelets are promoted based on the damage of the blood vessel tissueincluding endothelial cells and the unbalanced systemicfibrinolysis-coagulation equilibrium caused by the medicines itself, andthe like. For instance, it has been clarified that, after thecirculation of the blood has been restored by thrombolytic therapy usingt-PA (tissue Plasminogen Actitor) or the like, the fibrinolytic activityand the coagulating activity are activated to break the systemicfibrinolysis-coagulation equilibrium. Clinically, it causes re-occlusionand is therefore seriously problematic in the therapy (see J. Am. Coll.Cardiol., 12, 616-623, 1988). On the other hand, a PTCA Percutaneoustransluminal coronary angioplasty) therapy has been rapidly popularized,with producing good results in some degree, for curing disorders asbased on coronary stenosis and aortostenosis, such as stenocardia,myocardial infarction, etc. However, this therapy involves seriousproblems in that it damages the blood vessel tissue includingendothelial cells to cause acute coronary obstruction and evenre-stenosis which occurs in about 30% of therapeutical cases. Bloodplatelets play the principal role in various thrombotic disorders (e.g.,re-occlusion) following such blood circulation-restoring therapy.Therefore, the effectiveness of anti-platelet agents would be expectedfor such disorders. However, conventional anti-platelet agents have notas yet been verified to be satisfactorily effective. GPIIb/IIIa is aplatelet membrane glycoprotein which is one of the integrin family (seeBlood, 80, 1386-1404, 1992). This integrin binds to adhesive proteinssuch as fibrinogen, von Willebrand factor, etc., and have an importantfunction at the terminal in blood platelet aggregation. Monoclonalantibodies against GPIIb/IIIa, peptides having an RGD sequence and thelike have potent platelet aggregation inhibiting activity, and some ofwhich have already been put into clinical examinations.

Non-peptidic, low molecular weight GPIIb/IIIa antagonists are known in apublished Japanese patent application (kokai) 4-288051 (sulfonamidefibrinogen receptor antagonists of the following representativecompound, ##STR2## and a published Japanese patent application (kokai)6-25227 (cyclic imino derivatives of the following representativecompound, ##STR3## and are disclosed by Leo et al. (see Journal ofMedicinal Chemistry, 35, 4393-4407, 1992) in which the followingrepresentative compound is disclosed. ##STR4## The piperizine aceticacid derivatives of the following general formula are disclosed in apublished PCT patent application WO093/10091. ##STR5## (in which X¹ andy¹, which may be the same or different, represent CH or N;

X² represents CH or, when X¹ represents CH, may also represent N;

y² represents N or, when y¹ represents N, may also represent CH;

z represents N or N⁺ R⁵ ;

R¹ represents a hydrogen atom or a hydroxyl, C₁₋₄ alkyl or2,2,2-trifluoroethyl group;

R² represents a hydrogen atom or, when both X¹ and X² represent CH, mayalso represent a fluorine, chlorine or bromine atom or a C₁₋₄ alkylgroup;

R³ represents a hydrogen atom or, when both Y¹ and y² represent N, mayalso represent a C₁₋₄ alkyl or hydroxymethyl group;

R⁴ represents a hydrogen atom or, when Z represents N, R⁴ may alsorepresent a C₁₋₄ alkyl group;

R⁵ represents a C₁₋₄ alkyl or phenyl C₁₋₄ alkyl group;

R⁶ represents a hydrogen atom or a C₁₋₄ alkyl group.)

However, the compounds in the above application is disclosed as plateletaggregation inhibitor. GPIIb/IIIa antagonists having wide safety rangeand a definite effect through oral administration are highly desired.

DISCLOSURE OF THE INVENTION

The present inventors created novel benzamidine derivatives of thefollowing formula and found that the derivatives have excellentGPIIb/IIIa antagonizing activity, and filed a patent application(Japanese patent application No. Hei-8-333342(kokai). ##STR6## (whereinR¹ and R.sup. are the same or different and each represents a hydrogenatom or an ester residue;

X¹ represents a lower alkylene group;

X² represents a single bond or a lower alkylene group;

m represents 0, 1, or 2;

n represents 0 or 1, provided that n=1 when m=0.).

As a result of further extensive studies, it was found that novelsubstituted-amidinobenzene derivatives obtained by changing theseamidinobenzene derivatives to prodrugs at the amidino group haveextremely excellent peroral absorbability and sustainment of the effect,resulting in accomplishment of the present invention.

Thus, the present invention relates to the substituted-amidinobenzenederivatives of the following general formula (I) and their salts, aswell as pharmaceutical compositions comprising such compounds along withpharmaceutically acceptable carriers. ##STR7## (the symbols in the aboveformula have the following meanings: R¹ : a group which can be convertedinto an amidino group in vivo;

R² and R³ : the same or different and each represents a carboxyl groupor a group which can be converted into a carboxyl group in vivo;

X¹ and X² : the same or different and each represents a lower alkylenegroup;

m: 0, 1 or 2;

n: 0 or 1, provided that n=1 when m=0. The same applies hereinafter.)

The compounds of the present invention are structurally characterized inthat the substituent R¹ on benzene is a group which can be convertedinto an amidino group in vivo and thus the compounds are prodrugs. Asdescribed below, such change into prodrugs achieved extremely excellentperoral absorbability and accompanying sustained effects. The secondcharacteristics is that (1) the compounds have two carboxyl group orgroup which can be converted into a carboxyl group in vivo on thepiperidine ring and/or (2) the compounds have one or two oxo groups onthe piperazine ring. The compounds of the present invention haveexcellent GPIIb/IIIa antagonizing effect based on such a structure.

Preferable compounds among the compounds of the present invention in thegeneral formula (I) shown above are:

the substituted-amidinobenzene derivatives or salts thereof, wherein atleast one of R² and R³ is a group which can be converted into a carboxylgroup in vivo (i.e., the compounds which have been made into prodrugs atboth of the amidino group and the carboxyl group (so-called doubleprodrug compounds));

the substituted-amidinobenzene derivatives or salts thereof, wherein thegroup which can be converted into an amidino group in vivo of R¹ is agroup selected from the group consisting of a hydroxyamidino group, alower alkoxycarbonylamidino group, a lower alkoxyamidino group and alower alkanoylamidino group;

the substituted-amidinobenzene derivatives or salts thereof, wherein thegroup which can be converted into an carboxyl group in vivo of R² and R³is a group selected from the group consisting of a lower alkoxycarbonylgroup, a lower alkoxy-lower alkoxycarbonyl group, a lower alkoxy-loweralkoxy-lower alkoxycarbonyl group, a halogeno-lower alkoxylcarbonylgroup, a lower alkenyloxycarbonyl group, a lower alkanoyloxy-loweralkoxycarbonyl group, a lower alkenoyloxy-lower alkoxycarbonyl group, alower alkanoyl-lower alkoxycarbonyl group, a lower alkenoyl-loweralkoxycarbonyl group, a lower alkoxy-lower alkanoyloxy-loweralkoxycarbonyl group, a lower alkoxycarbonyloxy-lower alkoxycarbonylgroup, a lower alkoxy-lower alkoxycarbonyloxy-lower alkoxycarbonylgroup, di-lower alkylamino-lower alkoxycarbonyl group, acycloalkyloxycarbonyloxy-lower alkoxycarbonyl group, a loweralkoxybenzyloxycarbonyl group, a nitrobenzyloxycarbonyl group, a loweralkoxybenzhydryloxycarbonyl group, a benzhydryloxycarbonyl group, abenzoyloxy-lower alkoxycarbonyl group, a2-oxotetrahydrofuran-5-yloxycarbonyl group, a2-oxo-5-alkyl-1,3-dioxolen-4-ylmethoxycarbonyl group, atetrahydrofuranylcarbonyloxymethoxycarbonyl group, and a3-phthalidyloxycarbonl group; and

the substituted-amidinobenzene derivatives or salts thereof, whereinm=1.

Still preferable compounds are the substituted-amidinobenzenederivatives or salts thereof, wherein m=1 and n=0.

Particularly preferable compounds are the compounds shown below or saltsthereof.

Ethyl4-[4-(4-hydroxylamidinophenyl)-3-oxo-1-piperazinyl]-1-piperidineacetate,methyl4-[4-(4-hydroxylamidinophenyl)-3-oxo-1-piperazinyl]-1-piperidineacetate,ethyl4-[4-(4-methoxycarbonylamidinophenyl)-3-oxo-1-piperazinyl]-1-piperidineacetate,methyl4-[4-(4-methoxycarbonylamidinophenyl)-3-oxo-1-piperazinyl]-l-piperidineacetate,and ethyl4-[4-(4-ethoxycarbonylamidinophenyl)-3-oxo-1-piperazinyl]-1-piperidineacetate.Among these compounds, the most preferable compound is ethyl4-[4-(4-hydroxylamidinophenyl)-3-oxo-1-piperazinyl]-1-piperidineacetateor salts thereof.

Other preferable compounds include the substituted-amidinobenzenederivatives or salts thereof, wherein m=0 and n=1, particularly thesubstituted-amidinobenzene derivatives or salts thereof wherein both ofR² and R³ are a group which can be converted into a carboxyl group invivo.

Hereinafter, the compounds (I) of the present invention are described indetail.

Unless otherwise specifically indicated, the term "lower" as referred toherein for the definitions of the general formulae given herein isdirected to a linear or branched carbon chain having from 1 to 6 carbonatoms.

Accordingly, the "lower alkylene group" represented by X¹ and X² in thegeneral formula (I) is suitably a linear or branched alkylene grouphaving from 1 to 6 carbon atoms, and its illustrative examples include amethylene group, an ethylene group, a methylmethylene group, atrimethylene group, a propylene group, a 2-propylene group, adimethylmethylene group, a tetramethylene group, a 1-methyltrimethylenegroup, a 2-methyltrimethylene group, a 3-methyltrimethylene group, a1-ethylethylene group, a 2-ethylethylene group, a 2,2-dimethylethylenegroup, a 1,1-dimethylethylene group, an ethylmethylmethylene group, apropylmethylene group, a pentamethylene group, a 1-methyltetramethylenegroup, a 2-methyltetramethylene group, a 3-methyltetramethylene group, a4-methyltetramethylene group, a 1,1-dimethyltrimethylene group, a2,2-dimethyltrirethylene group, a 3,3-dimethyltrimethylene group, a1,3-dimethyltrimethylene group, a 2,3 -dimethyltrimethylene group, a1,2-dimethyltrimethylene group, a 1-ethyltrimethylene group, a1,1,2-trimethylethylene group, a diethylmethylene group, a1-propylethylene group, a 2-propylethylene group, a butylmethylenegroup, a hexamethylene group, a 1-methylpentamethylene group, a1,1-dimethyltetramethylene group, a 2,2-dimethyltetramethylene group, a3,3-dimethyltetramethylene group, a 4,4-dimethyltetramethylene group, a1,1,3-trimethyltrimethylene group, a 1,1,2-trimethyltrimethylene group,a 1,1,2,2-tetramethylethylene group, a 1,1-dimethyl-2-ethylethylenegroup, a 1,1-diethylethylene group, a 1-propyltrimethylene group, a2-propyltrimethylene group, a 3-propyltrimethylene group, a1-butylethylene group, a 2-butylethylene group, a1-methyl-1-propylethylene group, a 2-methyl-2-propylethylene group, a1-methyl-2-propylethylene group, a 2-methyl-propylethylene group, apentylmethylene group, a butylmethylmethylene group, anethylpropylmethylene group, and the like. Among these groups, straightalkylene groups of 1 to 3 carbon atoms are preferable, and a methylenegroup and an ethylene group are the most preferable.

The "group which can be converted into an amidino group in vivo" of R¹and the "group which can be converted into a carboxyl group in vivo" ofR² and/or R³ are the groups which constitute the compound which can bean active body of medicines, or a group constituting an amidine prodrugwhich can be metabolized in vivo to become an amidine compound as anactive body in the former case or a group constituting a carboxylic acidprodrug which can be metabolized in vivo to form a carboxylic acidcompound as an active body in the letter case.

The "group which can be converted into an amidino group in vivo" and the"group which can be converted into a carboxyl group in vivo" can beeasily determined by administering the compound of the present inventionto human or other animals and analyzing the metabolized product byordinary analytical techniques. That is, the former can be detected as acompound having an amidino group after metabolism in vivo and the lattercan be detected as a compound having a carboxyl group after metabolismin vivo.

Accordingly, the "group which can be converted into an amidino group invivo" of R¹ includes substituted amidino groups which can be hydrolyzedby metabolism in vivo, i.e., those constituting an amidino group-basedprodrug. The substituted amidino group include a hydroxyamidino group, alower alkoxycarbonylamidino group, a lower alkoxyamidino group and alower alkanoylamidino group. A hydroxyamidino group and a loweralkoxycarbonylamidino group are preferable, and a hydroxyamidino groupis particularly preferable.

The "group which can be converted into a carboxyl group in vivo" of R²and/or R³ includes substituted carboxyl groups which can be hydrolyzedby metabolism in vivo, i.e., those constituting a carboxyl group-basedprodrug. The substituted carboxyl group include an unsubstituted loweralkoxy-carbonyl group and straight-chain substituted loweralkoxycarbonyl groups, e.g., a lower alkoxy-lower alkoxycarbonyl group,a lower alkoxy-lower alkoxy-lower alkoxycarbonyl group, a halogeno-loweralkoxylcarbonyl group, a lower alkenyloxycarbonyl group, a loweralkanoyloxy-lower alkoxycarbonyl group, a lower alkenoyloxy-loweralkoxycarbonyl group, a lower alkanoyl-lower alkoxycarbonyl group, alower alkenoyl-lower alkoxycarbonyl group, a lower alkoxy-loweralkanoyloxy-lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-loweralkoxycarbonyl group, a lower alkoxy-lower alkoxycarbonyloxy-loweralkoxycarbonyl group, and di-lower alkylamino-lower alkoxycarbonylgroup, and a cycloalkyloxycarbonyloxy-lower alkoxycarbonyl group, alower alkoxybenzyloxycarbonyl group, a nitrobenzyloxycarbonyl group, alower alkoxybenzhydryloxycarbonyl group, a benzhydryloxycarbonyl group,a benzoyloxy-lower alkoxycarbonyl group, a2-oxotetrahydrofuran-5-yloxycarbonyl group, a2-oxo-5-alkyl-1,3-dioxolen-4-ylmethoxycarbonyl group, atetrahydrofuranylcarbonyloxymethoxycarbonyl group, and a3-phthalidyloxycarbonl group. Preferable groups are an unsubstitutedlower alkoxycarbonyl group and the straight-chain substituted loweralkoxycarbonyl groups, e.g., a lower alkoxy-lower alkoxycarbonyl group,a lower alkoxy-lower alkoxy-lower alkoxycarbonyl group, a halogeno-loweralkoxylcarbonyl group, a lower alkenyloxycarbonyl group, a loweralkanoyloxy-lower alkoxycarbonyl group, a lower alkenoyloxy-loweralkoxycarbonyl group, a lower alkanoyl-lower alkoxycarbonyl group, alower alkenoyl-lower alkoxycarbonyl group, a lower alkoxy-loweralkanoyloxy-lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-loweralkoxycarbonyl group, a lower alkoxy-lower alkoxycarbonyloxy-loweralkoxycarbonyl group, and di- lower alkylamino-lower alkoxycarbonylgroup, and a cycloalkyloxycarbonyloxy-lower alkoxycarbonyl group, a2-oxo-5-alkyl-1,3-dioxolen-4-ylmethoxycarbonyl group, and a3-phthalidyloxycarbonl group. A lower alkoxycarbonyl group is morepreferable, and a methoxycarbonyl group and an ethoxycarbonyl group areparticularly preferable.

The "lower alkyl group" includes, for example, a methyl group, an ethylgroup, a propyl group, an isopropyl group, a butyl group, an isobutylgroup, a sec-butyl group, a tert-butyl group, a pentyl group, anisopentyl group, a neopentyl group, a tert-pentyl group, a 1-methylbutylgroup, a 2-methylbutyl group, a 1,2-dimethylpropyl group, a hexyl group,an isohexyl group, a 1-methylpentyl group, a 2-methylpentyl group, a3-methylpentyl group, a 1,1-dimethylbutyl group, a 1,2-dimethylbutylgroup, a 2,2-dimethylbutyl group, a 1,3-dimethylbutyl group, a2,3-dimethylbutyl group, a 3,3-dimethylbutyl group, a 1- ethylbutylgroup, a 2-ethylbutyl group, a 1,1,2-trimethylpropyl group, a1,2,2-trimethylpropyl group, a 1-ethyl-1-methylpropyl group, a1-ethyl-2-methylpropyl group, and the like.

The "lower alkoxy group" corresponds to a hydroxyl group of which ahydrogen atom is substituted by the above-described lower alkyl group,such as a methoxy group, an ethoxy group, a propoxy group, an isopropoxygroup, a butoxy group, an isobutoxy group, a sec-butoxy group, atert-butoxy group, a pentyloxy (amyloxy) group, an isopentyloxy group, atert-pentyloxy group, a neopentyloxy group, a 2-methylbutoxy group, a1,2-dimethylpropoxy group, a 1-ethylpropoxy group, a hexyloxy group, andthe like, preferably a methoxy group, an ethoxy group, and a tert-butoxygroup.

The "lower alkanoyl group" is preferably those having 2 to 6 carbonatoms (e.g., acetyl, propionyl, pivaloyl, and the like); the "loweralkenoyl group" is preferably those having 3 to 6 carbon atoms (anacryloyl group, a crotonoyl group, a maleoyl group, and the like); the"cycloalkyl group" is preferably those having 3 to 8 carbon atoms,particularly those having 3 to 6 carbon atoms (e.g., cyclopropyl,cyclopentyl, cyclohexyl, and the like).

The "lower alkenyl group" is preferably those having from 2 to 6 carbonatoms (e.g., a vinyl group, an allyl group, a 1-propenyl group, and thelike).

The "halogeno-lower alkyl group" corresponds to the above-mentionedlower alkyl group of which one or more hydrogen atoms is/are substitutedby halogen atom(s) and includes a fluoromethyl group, a chloromethylgroup, a bromomethyl group, an iodomethyl group, a 1-chloroethyl group,a 2-chloroethyl group, a dichloromethyl group, a trifluoromethyl group,a dichlorobromomethyl group, and the like.

In the basic skeleton of the compound (I) of the present invention, themoiety represented by the formula ##STR8## means an oxopiperazine ringor a dioxopiperazine ring.

The illustrative examples of the oxopiperazine ring according to thepresent application are shown below. ##STR9## Among these rings, thering represented by ##STR10## is preferably and the ring represented by##STR11## is particularly preferable.

The compounds (I) of the present invention have at least one asymmetriccarbon atom, depending on the skeletal piperidinyl group and itssubstituent (a group of --X² --R³). Depending on the other substituents,the compounds (I) may have additional asymmetric carbon atom(s). Thecompounds of the present invention may exist in the form of opticalisomers, depending on these asymmetric carbon atoms. In addition, theyexist in the form of tautomeric isomers depending on the carbonyl groupsor the amidino groups in the substituents and also in the form ofgeometric isomers depending on the double bonds. The present inventionencompasses all isolated isomers of these optical isomers, tautomericisomers, and geometric isomers as well as their mixtures.

The compounds (I) of the present invention may be formed into salts.Examples of the preferred salts include alkali metal or alkaline earthmetal salts such as sodium salts, potassium salts, and calcium salts;hydrogen halides such as hydrofluorides, hydrochlorides, hydrobromides,and hydroiodides; salts with inorganic acids, such as carbonates,nitrates, perchlorates, sulfates, and phosphates; lower alkylsulfonatessuch as methanesulfonates, trifluoromethanesulfonates, andethanesulfonates; arylsulfonates such as benzenesulfonates andp-toluenesulfonates; salts with organic acids, such as fumarates,succinates, citrates, tartrates, oxalates, and maleates; salts withamino acids, such as glutamates and aspartates.

In addition, the present invention also encompasses hydrates andpharmaceutically acceptable solvates of compounds (I) as well aspolymorphic isomers of the compounds (I) of the present invention. As amatter of course, the present invention is not limited to only thecompounds of the Examples to be mentioned hereinafter but encompassesall substituted-amidinobenzene derivatives of the general formula (I)and their pharmaceutically acceptable salts.

(Production Methods)

Some typical production methods for the compounds of the presentinvention are explained below. First Production Method ##STR12##

(In the formula, R², R³, X¹, X², m and n have the same meanings asabove. R^(1a) means a hydroxyamidino group (or a lower alkoxy amidinogroup).

The compound (Ia) of the present invention can be produced by reactingthe nitrile compound (II) with hydroxylamine hydrochloride (or a loweralkoxyamine hydrochloride) in an appropriate solvent in the presence ofa base. The appropriate solvent is preferably those inert to thereaction and examples of such inert solvents include methanol, ethanol,dimethylformamide (DMF), dimethylacetamide, tetrachloroethane,dichloromethane, dichloroethane, chloroform, carbon tetrachloride,tetrahydrofuran (THF), dioxane, dimethoxymethane, diethoxymethane, ethylacetate, benzene, toluene, acetonitrile, dimethylsulfoxide (DMSO), etc.,and mixed solvents thereof. The solvent is appropriately selecteddepending on the various reaction conditions.

Examples of the base include sodium, sodium hydride, sodium methoxide,sodium ethoxide, potassium carbonate, triethylamide, pyridine, and thelike. Examples of the base preferably used in this reaction includetriethylamine, sodium methoxide, and sodium ethoxide.

The reaction may be carried out normally under room temperature, withheating, or with heating under reflux, and preferably with heating underreflux.

Second Production Method ##STR13##

(In the formula, R², R³, X¹, X², m and n have the same meanings asabove. R⁴ means a lower alkoxycarbonyl groups (or a lower alkanoylgroup). R^(1b) means a lower alkoxycarbonylamidino group (or a loweralkanoyl amidino group). Y means a releasable group such as a halogenatom, a hydroxyl group, a lower alkoxy group, a phenoxy group, animidazolyl group, an arylsulfonyloxy group, and a leaving group of anactive carboxylic acid derivative.)

The compound (Ib) of the present invention can be produced by reactingthe amidino compound (III) with a compound (IV) in the presence of anappropriate base. Examples of the appropriate base include thosedescribed above, and preferably sodium hydroxide, potassium carbonate,and triethylamine. Solvents may be used in this reaction and, examplesof the solvents to be used include those described above. Examples ofthe preferable solvents include layered solvent ofwater-dichloromethane, THF, DMF, and the like.

The active carboxylic acid derivative includes active esters to beobtained by the reaction with a phenol compound such as p-nitrophenol orthe like, or with an N-hydroxyamine compound such asN-hydroxysuccinimide, 1-hydroxy-benzotriazole or the like; mixed acidanhydrides to be obtained by the reaction with a monoalkyl carbonate oran organic acid, and mixed phosphoryl anhydrides to be obtained byreaction with diphenylphosphoryl chloride and N-methylmorpholine; acidazides to be obtained by reacting an ester with hydrazine or an alkylnitrite; acid halides such as acid chlorides, acid bromides, etc.;symmetric acid anhydrides, etc.

(Other Production Methods)

Among the compounds (I) of the present invention, those having acarboxyl group as R² and/or R³ can be obtained by dissolving thecorresponding compounds having a group which can be converted into acarboxyl group in vivo as R² and/or R³, in an appropriate solventfollowed by ordinary hydrolysis of ester under basic conditions, acidicconditions or neutral conditions.

Examples of the base to be used under basic conditions include sodiumhydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, andthe like. Examples of the acid to be used under acidic conditionsinclude Lewis acids (e.g., hydrochloric acid, sulfuric acid, borontrichloride), trifluoroacetic acid, p-toluenesulfonic acid. Underneutral conditions, halogen ions (e.g., lithium iodide and lithiumbromide), alkali metal salts (e.g., thiol and selenol),iodotrimethylsilane, and enzymes (e.g., esterase) may be used.

Examples of the solvent to be used in the reaction include water,alcohol (e.g., methanol and ethanol), acetone, dioxane, acetonitrile,tetrahydrofuran, N,N-dimethylformamide, dimethylsulfoxide, formic acid,acetic acid, pyridine, lutidine, collidine, and the like. Theabove-described commonly used solvents may be used as a mixture withwater.

The reaction normally proceeds under room temperature but sometimesshould be carried out under ice-cooling or with heating, and thus thereaction is carried out under the appropriately selected temperature.

Selecting the conditions for the hydrolysis appropriately,substituted-carboxylic acid compounds having only one carboxyl group.For example, an ester compound in which one ester residue is easilyhydrolyzed under acidic conditions (for example, tert-butyl group or thelike) and the other ester residue is easily hydrolyzed under basicconditions (for example, methyl ester, ethyl ester or the like) ishydrolyzed under selected conditions (acidic or basic conditions),whereby only one of the two ester residues is selectively hydrolyzed.

If desired, carboxylic acid compounds can further be esterified to givedesired esters. The esterification can be effected in any ordinarymanner under suitably selected conditions.

Compounds of the present invention where R² and/or R³ are/is the groupwhich can be converted into a carboxyl group in vivo can also beobtained by interesterification with suitable alcohols. For example, alarge excess amount of an alcohol is used for the interesterification tobe carried out in the presence of an acid or a base or any othercatalyst (for example, titanium (IV) alkoxide) or the other alcohols tobe formed during the reaction are removed out of the reaction system,thereby shifting the equilibrium of the reaction toward the system ofproducing the desired ester compound.

(Methods for Producing Compounds of Starting Compounds)

Next, methods for preparing the compounds to be used as startingcompounds are described below.

Production Method A ##STR14## (In the formula, R³, R⁴, X¹, and X² havethe same meanings as mentioned above.)

The compound (VII) may be obtained by dissolving a compound (VI) in anappropriate solvent followed by reaction with an appropriate secondaryamine to give an enamine, and then allowing alkyl acrylate (e.g., methylacrylate) or halogenated alkyl (e.g., ethyl bromoacetate) to act on theenamine. The enamine may be used after isolation or without isolation.

Examples of the secondary amine include pyrrolidine, piperidine,morpholine, diethylamine, and diisopropylamine.

Examples of the solvent include toluene, benzene, chlorobenzene, and thelike. In addition to these commonly used solvents, the reaction may becarried out in any other organic solvents as long as the solvent doesnot cause bad influence on the reaction.

The reaction is carried out with removing water out of the system whichis formed when enamine is formed, by adding water-absorbing agents suchas potassium hydroxide, Molecular Sieves, etc. or by using Dean-StarkTrap (azeotropic dehydrate apparatus). The temperature for the reactionis preferably set to azeotropic or reflux temperature.

Production Method B ##STR15## (In the formula, R³, R⁴, X¹, X², m and nhave the same meanings as above.)

The compound (II) is obtained by dissolving a compound (VIII) in asuitable solvent followed by reacting it with an amine compound (IX) togive a Schiff base, which is then reduced after isolation or withoutisolation.

The solvent is an organic solvent inert to the reaction, including, forexample, benzene, toluene, xylene, methanol, ethanol, isopropanol,methylene chloride, dichloroethane, chloroform, acetic acid, and thelike.

The reaction is conducted in such a way that a compound (VIII) isreacted with a reaction-corresponding amount of an amine compound (IX)or, alternatively, using one of them in a somewhat excessive amount,preferably in the presence of an acid catalyst such as p-toluenesulfonicacid, adipic acid, oxalic acid, pyridine hydrochloride, acetic acid orthe like. Depending on the reaction conditions, the reaction isadvantageously carried out with removing water out of the system, byadding water-absorbing agents such as potassium hydroxide, MolecularSieves, etc. or by using Dean-Stark Trap (azeotropic dehydrateapparatus). The temperature for the reaction is usually under roomtemperature but may be set to azeotropic or reflux temperature dependingon the reaction conditions.

The reduction of Schiff base is carried out by adding a reducing agentsuch as a metal hydride complex (e.g., sodium borohydride, lithiumborohydride, sodium cyanoborohydride, and sodium triacetoxyborohydride),borane, or the like in a former step reaction solution. ProductionMethod C ##STR16## (In the formula, A¹ to A⁴ may be the same ordifferent and each is a carbonyl group or a methylene group; Y¹represents the same releasable group as Y, and Y² represents is the sameleaving group as Y¹ or a hydrogen atom.)

In this reaction, a compound (XI) is reacted with an amine compound (X)to produce a compound (XII). (1) When the compound (XI) above is analkyl derivative wherein Y² is a leaving group, and A⁴ is a methylenegroup.

This reaction may be carried out according to ordinary N-alkylation. Thereaction is carried out by stirring an amine compound (X) and areaction-corresponding amount of a compound (XI) in an inert solventwith cooling or under heating. To promote the reaction, it is desirableto add a base (for example, an inorganic base such as potassiumcarbonate, sodium carbonate, sodium hydride or the like, or an organicbase such as triethylamine or the like) to the reaction system.

(2) When the compound (XI) above is a carboxylic acid derivative whereinY² is a leaving group, and A⁴ is a carbonyl group

The amide compound (XII) is obtained by acylating an amine (X) with acarboxylic acid or its active derivative (XI) in a suitable solvent.

The active carboxylic acid derivative includes active esters describedabove in Second Production Method and an amide compound (XII) is alsoobtained by acylation in the a carboxylic acid (XI) and a condensingagent in a suitable solvent. The condensing agent to be used in thereaction is preferably N,N-dicyclohexylcarbodiimide (DCC),1-ethyl-3-(3-(N,N-dimethylamino)propyl)carbodiimide,carbonyldiimidazole, diphenylphosphorylazide (DPPA),diethylphosphorylazide or the like.

The reaction is usually carried out in a solvent under cooling or roomtemperature. The solvent to be used is organic solvents which do notparticipate in the reaction, such as dimethylformamide,dimethylacetamide, dioxane, tetrahydrofuran, diethyl ether,dichloroethane, chloroform, carbon tetrachloride, dimethoxymethane,dimethoxyethane, ethyl acetate, benzene, acetonitrile, dimethylsulfoxide, etc., and mixed solvents thereof. These organic solvents maybe appropriately selected depending on the method to be applied.Depending on the type of acylation, the reaction should sometimes becarried out under dehydrated conditions. In addition, depending on themethod to be applied, it is preferable for the smooth progress of thereaction to carry out the reaction in the presence of a base such asN-methylmorpholine, triethylamide, trimethylamine, pyridine, etc. or byusing such a base as a solvent.

(3) When the compound (XI) above is an aldehyde wherein Y² is a hydrogenatom, and A⁴ is a carbonyl group.

A compound (XII) is obtained by dissolving an aldehyde derivative (XI)in a suitable solvent, reacting it with an amine (X) and thereafterreducing the iminium ion produced. The reaction solvent, the reducingagent and the reaction conditions in the above-mentioned ProductionMethod B may be applied to this reaction.

Production Method D ##STR17## (In the formula, A¹ to A⁴, Y¹, and m havethe same meanings as above.)

To obtain a (di)oxopiperazine ring compound (IX) by cyclization, theprecursor (XII) is treated in a suitable solvent in the absence orpresence of a suitable catalyst. This reaction is carried out withice-cooling or at room temperature or under heating.

Examples of the solvents to be used include dimethylformamide,dimethylacetamide, dimethylsulfoxide, tetrachloroethane,dichloromethane, dichloroethane, chloroform, carbon tetrachloride,tetrahydrofuran, dioxane, dimethoxymethane, dimethoxyethane, benzene,chlorobenzene, toluene, water, acetic anhydride, alcohols, etc., whichare appropriately selected depending on the various reaction conditions.

Examples of the catalyst to be used include bases (e.g., sodium hydride,potassium hydride, n-butyllithium, sec-butyllithium, potassiumtert-butoxide, potassium bis(trimethylsilyl)amide, lithiumdiisopropylamide, sodium methoxide, sodium ethoxide, sodium hydroxide,potassium hydroxide, potassium carbonate, potassium hydrogencarbonate,sodium carbonate, sodium hydrogencarbonate, triethylamine,diisopropylethylamine, dimethylaminopyridine), salts (e.g., sodiumacetate and potassium acetate), and acids (e.g., sulfuric acid andhydrochloric acid).

Production Method E ##STR18## (In the formula, A¹ to A⁴, X¹, X², Y¹, Y²,R², R³, m and n have the same meanings as above.)

In the similar manner as described in Production Method B, the compound(X) and the compound (VII) are reacted to form a compound (XIII),

The solvent, catalyst, and the reaction conditions, etc. are the samewith those of the above-described Production Method B.

In the similar manner as described in Production Method C, the compound(XIV) is produced from the compound (XIII). The solvent, catalyst, andthe reaction conditions, etc. are the same with those of theabove-described Production Method C.

Cyclization to form (di)oxopiperazine ring can be carried out in thesame manner described in the Production Method D. The solvent, catalyst,and the reaction conditions, etc. are the same with those of theabove-described Production Method D.

Production Method F ##STR19##

(In the formula, R², R³, X¹, X², m, and n have the same meanings asabove.)

Compounds (III) having an amidino group can be produced according to anyof the following methods (i), (ii) and (iii).

(i) Method of Converting a Nitrile into an Imidate Followed byCondensing with an Amine:

A nitrile compound (II) is reacted with an alcohol such as methanol,ethanol or the like in the presence of a hydrogen chloride gas at from-40° C. to 0° C. to give an imidate, which is then reacted with ammoniaor an amine or amine salt such as ammonium carbonate, ammonium chloride,ammonium acetate or the like. As the solvent for the reaction, methanol,ethanol, acetone, tetrahydrofuran, or the like is used.

(ii) Method of Converting a Nitrile into a Thioamide and then into aThioimidate Followed by Condensing with an Amine:

A nitrile compound (II) is reacted with hydrogen sulfide in the presenceof an organic base such as methylamine, triethylamine, pyridine,picoline or the like to give a thioamide compound. The thioamidecompound can also be obtained by reacting a nitrile compound (II) withO,O-diethyl dithiophosphate in the presence of hydrogen chloride.

The thus-obtained thioamide compound is then reacted with a lower alkylhalide such as methyl iodide, ethyl iodide or the like to give athioimidate, which is then reacted with ammonia or an amine or aminesalt such as ammonium carbonate, ammonium chloride, ammonium acetate orthe like. As the solvent for the reaction, methanol, ethanol, acetone,tetrahydrofuran, ethyl acetate, or the like is used.

(iii) Method of Directly Adding an Amine, Amine Salt, Metal Amide orGrignard Reagent to a Nitrile:

A reagent such as ammonia, ammonium chloride with ammonia, ammoniumthiocyanate, alkylammonium thiocyanate, MeAl(Cl)NH₂, NaNH₂, (CH₃)₂ NMgBror the like is added to a nitrile compound (II) in an appropriatesolvent or without solvent. As the solvent, chloroform, methanol,ethanol, acetone, tetrahydrofuran, toluene, dimethylformamide, or thelike is used. Addition of a catalyst of a base such as sodium hydride orthe like or an acid such as aluminium chloride, p-toluenesulfonic acidor the like to the reaction system noticeably accelerates the reactionin some cases. The reaction may be carried out with cooling, or at roomtemperature, or under heating.

Production Method G ##STR20## (In the Formula, R², R³, X¹, X², and nhave the same meanings as above)

The cyclization to form an oxopiperazine ring compound (IIa) is carriedout by reacting a precursor (XIIIa) with glyoxal in an appropriatesolvent.

The reaction may be carried out with ice-cooling, under roomtemperature, or under heating.

Examples of the solvent to be used include mixed solvent oftetrahydrofuran-water, dimethylformamide, dimethyl sulfoxide,1-methyl-2-pyrrolidine, dioxane, dimethoxymethane, alcohols, etc., whichmay be selected appropriately depending on the various reactionconditions.

Production Method H ##STR21## (In the formula, A¹, A², X¹, X², Y², R²,R³ and n have the same meanings as above)

This reaction process is to obtain the compound (XIII) by reacting thecompound (XV) and the amine compound (XVI).

1) When Y² is Y¹ and A² is a methylene group in the compound (XV) above,the reaction is carried out in the similar manner as described in 1) ofProduction Process C.

2) When Y² is Y¹ and A² is a carbonyl group in the compound (XV) above,the reaction is carried out in the similar manner as described in 2) ofProduction Process C.

3) When Y² is a hydrogen atom and A² is a carbonyl group in the compound(XV) above, the reaction is carried out in the similar manner asdescribed in 3) of Production Process C.

The compounds of the present invention as produced in the mannermentioned above are isolated and purified by any ordinary chemicaloperation which includes, for example, extraction, precipitation,fractional chromatography, recrystallization, and the like. In addition,the compounds of the present invention can be led into desired salts byordinary salt-forming reaction.

Industrial Applicability

The compounds of the present invention are useful as orally-applicableGPIIb/IIIa receptor antagonists, especially platelet aggregationinhibitor, including, for example, medicines for ameliorating ischemiccardiac disorders (anxiety stenocardia, acute myocardial infarction),and also for prevention of the following secondary complications,postoperative re-obstruction and re-stenosis following coronary arterybypass or PTCA, as well as for promotion of coronary thrombolysis andprophylaxis of re-obstruction following coronary thrombolysis, etc.); asadminicula in cardiosurgery operations or in vascular surgeryoperations; as medicines for ameliorating cerebrovascular disorders(transient ischemic attack (TIA), cerebral infarction, subarachnoidhemorrhage (vascular twitch), etc.); and as medicines for amelioratingperipheral artery disorders (chronic arterial obstruction, etc.).

Since the compounds of the present invention have especially useful as aprodrug of compounds in our previous application (an unexaminedpublished Japanese patent application No. 8-333342) and are thereforeuseful as medicines for ameliorating the above-mentioned disorders notonly by parenteral administration such as, for example, intravascularinjection but also by peroral administration. In addition, since plasmaresidence time of Compound A is prolonged by the administration of thecompounds of the present invention as a prodrug, the pharmaceuticaleffects of the compounds of the present invention is long acting, andthe clinical usefulness of the compounds is high. Moreover, the toxicityof the compounds of the present invention is much lower than that ofconventional compounds.

The platelet aggregation-inhibiting effect of the compounds of thepresent invention and usefulness as the prodrug have been confirmed bythe following test methods:

Metabolic Test of an Active Body (Compound A) in Plasma

Compound of Example 2 of the present invention was administered to threebeagle dogs orally at a dose of 10 mg/kg as an aqueous solution and thenblood was withdrawn over 48 hours after administration. Aftercentrifugation, plasma was separated and then stored at -20° C. untilanalysis. Compound A (compound name:4-[4-(4-amidinophenyl)-3-oxo-1-piperazinyl]-1-piperidineacetic acid, anunexamined published Japanese patent application No. 8-333342), which isan active body produced as a metabolite of Compound of Example 2, wasdetermined by the high performance liquid chromatography method toobtain the pharmacokinetic parameters. Compound A was also administeredto the same beagle dogs at a dose of 10 mg/kg, and then plasma CompoundA concentration was measured. Pharmacokinetic parameters of Compound Aafter the administration of Compound of Example 2 and Compound A werecompared-with each other. In Table 1 it is shown the pharmacokineticparameters of plasma Compound A after oral administration, and in FIG. 1it is shown the plasma concentration-time profile of Compound A afteroral administration.

Table 1 represents Pharmacokinetic parameters of plasma Compound A afteroral administration of Compound of Example 2 and Compound A to beagledogs at a dose of 10 mg/kg (mean of three animals±standard deviation)and FIG. 1 represents plasma concentration-time profile of Compound A.

                  TABLE 1                                                         ______________________________________                                                 C.sub.max T.sub.max AUC.sub.0-48                                                                           t.sub.1/2                                 Drug (ng/ml) (hr) (ng · hr/ml) (hr)                                ______________________________________                                        Compound of                                                                            532 ± 29                                                                             5.3 ± 1.2                                                                            13535 ± 459                                                                         19.6 ± 1.8                             Example 2                                                                     Compound A 748 ± 175 1.7 ± 0.6  3550 ± 838  2.1 ± 0.0           ______________________________________                                         (where C.sub.max is the maximum plasma concentration, T.sub.max is the        time to reach C.sub.max, AUC.sub.0-48 is the area under the                   timeconcentration curve in plasma over 48 hours after administration,         t.sub.1/2 is the elimination half life.)                                 

The area under the time-concentration curve in plasma of Compound Aafter the administration of Compound of Example 2 was over 3 timeshigher than that after the administration of Compound A. The t_(1/2) ofCompound A also greatly prolonged when it was orally administered asCompound of Example 2. It is confirmed that not only bioavailability butalso plasma residence time of Compound A increase when it isadministered as Compound of Example 2 which is designed for a doubleprodrug of Compound A.

Ex Vivo Platelet Aggregation-Inhibiting Activity in Cynomolgus Monkeys

Cynomolgus monkeys that had been lightly anesthetized by intramuscularadministration of ketamine hydrochloride were fixed on a work-bench, anda sample compound of the present invention dissolved or suspended in amethylcellulose solution was administered into the stomach via a stomachtube at a dose of 1 mg/kg. Before the administration and after theadministration at a predetermined period of time, 3 ml (containing 1/10times by volume of sodium citrate) of the blood was collected from theanimal through the femoral vein. From the blood, platelet-rich-plasma(PRP) was obtained according to the method of De Marco et al's (see J.clin. Invest., 77, 1272-1277, 1986). The PRP was adjusted at 3×10⁸ /mlwith an automatic blood cell counter (MEK-5158 Model, produced by NihonKoden Co.) before use. Then, 20 μM of ADP and 10 μg/ml of bovinetendon-derived collagen (produced by Niko Bioscience Co.) as triggers tocause the aggregation of the platelets. The degree of the aggregation ofthe platelets was measured with a platelet aggregation meter (NBSHematracer 801, produced by Niko Bioscience Co.). The plateletaggregation-inhibiting activity of the tested compound was representedby the inhibition percentage (%) relative to the maximum aggregationpercentage of each animal before the addition of the test compound.

The test results are shown in Table 2 together with the results of theCompound A which is the active body of the compounds of the presentinvention.

                                      TABLE 2                                     __________________________________________________________________________                            Platelet aggregation-inhibiting ratio                          after 3                                                                             after 6                                                                             after 9                                                                             after 12                                                                           after 24                                        Compound     n       hours            hours              hours                                                  hours             hours                   __________________________________________________________________________    Compound A                                                                           6 19.7 ± 9.4                                                                       16.3 ± 7.5                                                                       14.2 ± 5.9                                                                       ND   ND                                              Example 2    3  24.7 ± 23.7  66.3 ± 15.4   88.0 ± 11.0  89.0                                       ± 4.6    54.0 ± 9.0                       Example 7   3   9.0 ± 5.7   42.0 ± 14.7   60.0 ± 15.6  64.3                                        ± 8.7    26.0 ± 2.9                     __________________________________________________________________________     (ND: no data)                                                            

As shown in the above results, the compounds of the present inventionshowed excellent platelet aggregation-inhibiting ratio even incomparison with the active body compound A. In addition, the plateletaggregation-inhibiting ratio in the case of the prodrug compound of thepresent application was excellently maintained after 9, 12, and 24 hoursafter the administration, which confirmed that the compound showssufficient sustainment of the effect.

Incidentally, as described in our previous application, the active bodycompound in the present application has excellent effect to inhibitbinding of GPIIb/IIIa to fibrinogen and thus it per se has plateletaggregation-inhibiting effect. Accordingly, it is clear that thecompounds of the present invention, after absorption in viva, ismetabolized to become active body compound shown above as the results ofmetabolic test of an active body in plasma and shows plateletaggregation-inhibiting effect based on the effect to inhibit binding offibrinogen to GPIIb/IIIa.

As shown in the above pharmacological test results, the compounds of thepresent invention are excellent in bioavailability and in sustainment ofthe effect. Accordingly, it was confirmed that the compounds of thepresent invention are favorable-compounds as a prodrug, especially as adouble prodrug.

Pharmaceutical compositions comprising one or more of the compounds andtheir salts of the present invention as the active ingredient can beformulated along with carriers, excipients and other additives which aregenerally used in ordinary formulation.

The carriers and excipients to be used for the formulation may be solidor liquid, non-toxic pharmaceutically acceptable substances. Examples ofsuch carriers and excipients include lactose, magnesium stearate,starch, talc, gelatin, agar, pectin, gum arabic, olive oil, sesame oil,cacao butter, ethylene glycol and others which are ordinarily used inthe art.

The pharmaceutical composition can be administered either orally astablets, pills, capsules, granules, powders, liquids, etc., orparenterally as intravenous or intramuscular injections, suppositories,transdermal preparations, inhalants, intracystic injection, etc. Thedose of the composition is suitably determined for individual patients,depending on their conditions, ages, sexes, etc. In general, however,the oral dose to adults is approximately from 0.01 mg/kg/day to 100mg/kg/day, which is administered once at a time or in from 2 to 4portions. Where the composition is administered intravascularlydepending on the conditions of patients, the dose is, in general,approximately from 0.001 mg/kg to 10 mg/kg and is applied once toseveral times a day.

The solid composition for use in the oral administration according tothe present invention is used in the form of tablets, powders, granulesand the like. In such a solid composition, one or more active substancesare mixed with at least one inert diluent such as lactose, mannitol,glucose, hydroxypropylcellulose, microcrystalline cellulose, starch,polyvinyl pyrrolidone, metasilicic acid or magnesium aluminate. In theusual way, the composition may contain additives other than the inertdiluent, such as a lubricant (e.g., magnesium stearate), adisintegrating agent (e.g., calcium cellulose glycolate), a stabilizingagent (e.g., lactose) and a solubilization-assisting agent (e.g.,glutamic acid and aspartic acid). If necessary, tablets or pills may becoated-with a film of a gastric or enteric substance such as sucrose,gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalateor the like.

The liquid composition for oral administration includes pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, elixirs and thelike and contains a commonly used inert diluent such as purified wateror ethyl alcohol. In addition to the inert diluent, this composition mayalso contain auxiliary agents such as a moistening agent, a suspendingagent and the like, as well as sweeteners, flavors, aromas andantiseptics.

The injections for parenteral administration includes aseptic aqueous ornon-aqueous solutions, suspensions and emulsions. Examples of thediluent for use in the aqueous solutions and suspensions includedistilled water for injection use and physiological saline. Examples ofthe diluent for use in the non-aqueous solutions and suspensions includepropylene glycol, polyethylene glycol, a plant oil (e.g., olive oil), analcohol (e.g., ethyl alcohol), Polysorbate 80 and the like. Such acomposition may further contain additive agents such as an antiseptic, amoistening agent, an emulsifying agent, a dispersing agent, astabilizing agent (e.g., lactose) and a solubilization assisting agent(e.g., glutamic acid and aspartic acid). These compositions aresterilized by filtration through a bacteria-retaining filter, blendingof a germicide or irradiation. Alternatively, they may be used by makinginto sterile solid compositions and dissolving them in sterile water ora sterile solvent for injection prior to their use.

BEST MODES OF CARRYING OUT THE INVENTION

The present invention is described in more detail by means of thefollowing Examples. However, the compounds of the present invention arenot limited to only the compounds of the Examples but include all thecompounds of the above-mentioned general formula (I), their salts,hydrates, solvates, tautomers, geometric and optical isomers andpolymorphic isomers.

Reference Example 1

Methyl 4-oxo-3-piperidinecarboxylate hydrochloride (9.65 g), 21.0 g ofethyl bromoacetate and 24.0 g of potassium carbonate were dissolved in200 ml of N,N-dimethylformamide and the solution was stirred at roomtemperature overnight. Then, 100 ml of water was added to the reactionliquid, and the mixture was extracted with 500 ml of ethyl acetate. Theresulting extract was dried over sodium sulfate and concentrated. Theresulting residue was purified by silica gel column chromatography(eluent: chloroform) to give 9.0 g of ethyl3-ethoxycarbonylmethyl-3-methoxycarbonyl-4-oxo-1-piperidineacetate as anoily substance.

Mass spectrum (m/z): FAB (Pos) 330 (M⁺ +1)

NMR spectrum (CDCl₃, TMS internal standard): δ: 1.23-1.31 (6H, m),2.46-2.51 (1H, m), 2.71 (2H, dd), 2.91-2.96 (2H, m), 3.00-3.08 (2H, m),3.35-3.45 (2H, m), 3.79 (3H, s), 4.10-4.19 (4H, m)

Reference Example 2

Ethyl 3-ethoxycarbonylmethyl-3-methoxycarbonyl-4-oxo-1-piperidineacetate(1.0 g) and 140 mg of lithium chloride were dissolved in 10 ml ofN,N-dimethylformamide and the solution was refluxed for 48 hours. Then,10 ml of water was added to the reaction liquid, and the mixture wasextracted with 100 ml of ethyl acetate. The resulting extract was driedover sodium sulfate and concentrated. The resulting residue was purifiedby silica gel column chromatography (eluent: chloroform) to give 400 mgof diethyl 4-oxo-1,3-piperidinediacetate as an oily substance.

Mass spectrum (m/z): FAB (Pos.) 272 (M⁺ +1)

NMR spectrum (CDCl₃, TMS internal standard): δ: 1.23-1.30 (6H, m), 2.18(1H, dd), 2.36-2.40 (1H, m), 2.50 (1H, t), 2.70-2.77 (3H, m), 3.13-3.26(3H, m), 3.38 (2H, s), 4.09-4.22 (4H, m)

Reference Example 3

Diethyl 4-oxo-1,3-piperidinediacetate (28 g), 19 g of4-(1-piperazinyl)benzonitrile and 6 g of acetic acid were dissolved in250 ml of dichloromethane, 42 g of sodium triacetoxyborohydride wasadded, and the mixture was stirred at room temperature for 24 hours. Thereaction liquid was neutralized with an aqueous 1 N sodium hydroxidesolution and then the organic layer was separated. The organic layer wasdried over sodium sulfate and concentrated, and the resulting residuewas purified by silica gel chromatography (eluent: hexane:ethylacetate=1:1) to give 13 g of diethyl 4-[4-(4-cyanophenyl)-1-piperazinyl]-1,3-piperidineacetate.

Reference Example 4

Diethyl 4-[4-(4-cyanophenyl)-1-piperazinyl]-1,3-piperidineacetate (8.2g) was dissolved in 100 ml of ethanol, and hydrogen chloride was made toblown at from -10° C. to -20° C. until saturation. The solution washeated to room temperature and stirred overnight, and the solvent wasremoved by evaporation. The residue thus obtained was dissolved in 100ml of ethanol, 9.0 g of ammonium carbonate was added, and the mixturewas stirred at room temperature overnight. The solvent was removed fromthe reaction mixture by evaporation, and the resulting residue waspurified by silica gel column chromatography (eluent:chloroform:methanol =10:1) to give 4.4 g of diethyl4-[4-(4-amidinophenyl)-1-piperazinyl]-1,3-piperidineacetatehydrochloride.

Mass spectrum (m/z): FAB (Pos.) 460 (M⁺ +1)

NMR spectrum (DMSO-d₆, TMS internal standard): δ: 1.18 (6H, t),1.69-1.83 (3H, m), 2.01-2.33 (5H, m), 2.66-2.87 (3H, m), 3.08-3.23 (4H,m), 4.03-4.33 (4H, m), 7.06 (2H, d), 7.73 (2H, d)

Reference Example 5

N-(tert-Butoxycarbonyl)glycine (14.83 g) was dissolved in 50 ml oftetrahydrofuran, and 13.73 g of 1,1'-carbonylbis-1H-imidazole wasgradually added, and the mixture was stirred at room temperature for 3hours. Then, 10 g of p-aminobenzonitrile was added and the mixture wasstirred for 3 days. Then, the solvent was removed by evaporation under areduced pressure. Water was added to the resulting residue. The crystalsthus formed were collected by filtration, washed with a small amount ofethanol, and then dried under a reduced pressure to give 20.5 g of2-(tert-butoxycarbonylamino)-N-(4-cyanophenyl)acetamide.

Mass spectrum (m/z): FAB 276 (M+H)⁺

NMR spectrum (CDCl₃, TMS internal standard): δ: 1.49 (9H, s), 3.92 (2H,d), 5.18 (1H, brs), 7.61 (2H, d), 7.65 (2H, d), 8.59 (1H, brs)

Reference Example 6

An ethyl acetate solution (45.5 ml) of 4N hydrogen chloride solution wasadded to 10 g of 2-(tert-butoxycarbonylamino)-N-(4-cyanophenyl)acetamidein a closed vessel and the mixture was stirred for 18 hours. Thecrystals formed were collected by filtration, washed with ethyl acetateand then dried under a reduced pressure to give 7.7 g of2-amino-N-(4-cyanophenyl)acetamide hydrochloride. Then, 58.8 ml of anaqueous saturated sodium hydrogencarbonate solution and 20 ml of waterwere added to 3.7 g of the hydrochloride thus obtained, and the mixturewas stirred for 1 hour. The crystals thus formed were collected byfiltration and dried under a reduced pressure to give 2.5 g of2-amino-N-(4-cyanophenyl)acetamide.

Mass spectrum (m/z): FAB 176 (M+H)⁺

NMR spectrum (CDCl₃, TMS internal standard): δ: 1.68 (2H, brs), 3.50(2H, s), 7.61 (2H, d), 7.74 (2H, d), 9.75 (1H, brs)

Reference Example 7

2-Amino-N-(4-cyanophenyl)acetamide (1.83 g) was dissolved in 90 ml ofmethylene chloride, 3.10 g of ethyl 2-(4-oxo-1-piperidine)acetate, 4.4ml of acetic acid and 8.88 g of sodium triacetoxyborohydride were addedin that order, and the mixture was stirred for 1.5 hours. Afterconcentrating the mixture under a reduced pressure, water and sodiumcarbonate were added to make the system alkaline. Then, the crystalsformed were collected by filtration. The crude crystals were dissolvedin chloroform and washed with brine. The resulting organic layer wasdried over anhydrous sodium sulfate and filtered, and the resultingfiltrate was concentrated under a reduced pressure. Ether was added tothe resulting residue, and the solid formed was collected by filtrationto give 2.82 g of ethyl4-[N-(4-cyanophenyl)carbamoylmethylamino]-1-piperidineacetate.

Mass spectrum (m/z): APCI+QlMS: 345

NMR spectrum (CDCl₃, TMS internal standard): δ: 1.27 (3H, t), 1.50-1.58(2H, m), 1.67 (1H, brs), 1.88-1.90 (2H, m), 2.23-2.27 (2H, m), 2.49-2.54(1H, m), 2.95 (2H, m), 3.22 (2H, s), 3.42 (2H, s), 4.18 (2H, q), 7.62(2H, d), 7.72 (2H, d), 9.69 (1H, brs)

Reference Example 8

Sodium cyanoborohydride (0.48 g) and 0.57 g of acetic acid were added inthat order to a mixed solution of 1.0 g of ethyl4-[N-(4-cyanophenyl)carbamoylmethylamino]-1-piperidineacetate, 10 ml ofmethanol and 2.85 g of chloroacetaldehyde (40% aqueous solution), andthe mixture was stirred overnight. The solvent was removed byevaporation, chloroform was added, and the mixture was washed with anaqueous saturated sodium hydrogencarbonate solution. The resultingorganic layer was separated and concentrated under a reduced pressure.The resulting residue was subjected-to silica gel column chromatography(eluent: chloroform:methanol=100:1, v/v) to give 1.15 g of ethyl4-[N-(2-chloroethyl)-N-[N-(4-cyanophenyl)carbamoylmethyl]amino]-1-piperidineacetate.

Mass spectrum (m/z): FAB 407 (M+H)⁺

Reference Example 9

Ethyl4-[N-(2-chloroethyl)-N-[N-(4-cyanophenyl)carbamoylmethyl]amino]-1-piperidineacetate(1.08 g) was dissolved in 30 ml of N,N-dimethylformamide, 0.18 g ofsodium hydride (60% in oil) was gradually added, and the mixture wasstirred for 5 hours. An aqueous saturated ammonium chloride solution wasadded, and the solvent was removed by evaporation. Then, chloroform andan aqueous saturated sodium hydrogencarbonate solution were added, themixture was subjected to liquid-liquid separation, and the resultingorganic layer was concentrated under a reduced pressure. Ether was addedto the resulting residue, and the solid formed was collected byfiltration to give 0.43 g of ethyl4-[4-(4-cyanophenyl)-3-oxo-1-piperazinyl]-1-piperidineacetate.

Mass spectrum (m/z): FAB 371 (M+H)⁺

NMR spectrum (CDCl₃, TMS internal standard): δ: 1.28 (3H, t), 1.65-1.71(2H, m), 1.83-1.85 (2H, m), 2.24-2.28 (2H, m), 2.35-2.39 (1H, m),2.91-2.93 (2H, m), 3.01-3.04 (2H, m), 3.22 (2H, s), 3.46 (2H, s),3.71-3.73 (2H, m), 4.19 (2H, q), 7.49 (2H, d), 7.68 (2H, d)

In the same manner as in Reference Example 4, the compound of thefollowing Reference Example 10 was obtained.

Reference Example 10

Ethyl 4-[4-(4-amidinophenyl)-3-oxo-1-piperazinyl]-1-piperidineacetatehydrochloride

Starting compound: Ethyl 4-[4-(4-cyanophenyl)-3-oxo-51-piperazinyl]-1-piperidineacetate

Mass spectrum (m/z): FAB 388 (M+H)⁺

NMR spectrum (DMSO-d₆, TMS internal standard): δ: 1.19 (3H, t),1.43-1.47 (2H, m), 1.77-1.80 (2H, m), 2.17-2.21 (2H, m), 2.29 (1H, m),2.87-2.89 (4H, m), 3.19 (2H, s), 3.33 (2H, s), 3.70-3.72 (2H, d), 4.08(2H, q), 7.65 (2H, d), 7.84 (2H, d), 9.01 (2H, brs), 9.32 (2H, brs)

In the same manner as in Reference Example 9, the compound of thefollowing Reference Example 11 was obtained.

Reference Example 11

Methyl 4-[4-(4-cyanophenyl)-3-oxo-1-piperazinyl]-1-piperidineacetate

Starting compound: Methyl4-[N-(2-chloroethyl)-N-[N-(4-cyanophenyl)carbamoylmethyl]amino]-1-piperidineacetate

Mass spectrum (m/z): FAB (Pos.) 357 (M⁺ +1)

NMR spectrum (CDCl₃, TMS internal standard): δ: 1.63-1.73 (2H, m),1.83-1.86 (2H, m), 2.22-2.28 (2H, m), 2.33-2.41 (1H, m), 2.91-2.93 (2H,m), 3.00-3.03 (2H, m), 3.24 (2H, s), 3.46 (2H, s), 3.71-3.74 (5H, m),7.49 (2H, d), 7.68 (2H, d)

In the same manner as in Reference Example 4, the compound of thefollowing Reference Example 12 was obtained.

Reference Example 12

Methyl 4-[4-(4-amidinophenyl)-3-oxo-1-piperazinyl]-1-piperidineacetatehydrochloride

Starting compound: Methyl4-[4-(4-cyanophenyl)-3-oxo-1-piperazinyl]-1-piperidineacetate

Mass spectrum (m/z): FAB (Pos.) 374 (M⁺ +1)

NMR spectrum (DMSO-d₆, TMS internal standard): δ: 1.47 (2H, m),1.79-1.81 (2H, m), 2.21-2.31 (3H, m), 2.89 (4H, m), 3.34 (4H, m), 3.62(3H, s), 3.71-3.73 (2H, m), 7.65 (2H, d), 7.88 (2H, d), 9.28 (2H, brs),9.43 (2H, brs)

Reference Example 13

Ethyl 4-[[2-(4-cyanoanilino)ethyl]amino]-1-piperidineacetate (1.0 g) wasdissolved in a mixed solvent of 10 ml of tetrahydrofuran and 10 ml ofwater, 0.69 ml of glyoxal (40%, aqueous) was added, and the mixture wasstirred at room temperature for 15 hours. The solvent was evaporated andthe residue was extracted with ethyl acetate. The organic layer waswashed successively with an aqueous saturated sodium hydrogencarbonatesolution and brine. The organic layer was dried over anhydrous magnesiumsulfate and the solvent was evaporated. The resulting crude crystalswere recrystallized from toluene-hexane to give 0.86 g of ethyl4-[4-(4-cyanophenyl)-3-oxo-1-piperazinyl]-1-piperidineacetate.

Mass spectrum (m/z): FAB 371 (M+H)⁺

NMR spectrum (CDCl₃, TMS internal standard): δ: 1.28 (3H, t), 1.5-1.9(4H, m), 2.1-2.4 (3H, m), 2.9-3.1 (4H, m), 3.22 (2H, s), 3.46 (2H, s),3.7-3.8 (2H, m), 4.19 (2H, q), 7.48 (2H, d), 7.69 (2H, d)

EXAMPLE 1

Hydroxylamine hydrochloride (700 mg) was dissolved in 100 ml of ethanoland 680 mg of sodium ethoxide was added at room temperature. After 5minutes, 2.2 g of (±)-cis-diethyl4-[4-(4-cyanophenyl)-1-piperazinyl]-1,3-piperidineacetate was added, andthe mixture was refluxed overnight. The reaction solution wasconcentrated, 200 ml of water was added, and the mixture was extractedwith 300 ml of chloroform. The extract was dried over sodium sulfate,concentrated, and then purified by silica gel column chromatography(eluent: chloroform:methanol=50:1 to 20:1) to give 1.5 g of (±)-cis-diethyl4-[4-(4-hydroxyamidinophenyl)-1-piperazinyl]-1,3-piperidineacetate.

Mass spectrum (m/z): FAB (Pos.) 476 (M⁺ +1)

NMR spectrum (CDCl₃, TMS internal standard): δ: 1.24-1.28 (6H, m),1.76-1.78 (1H, m), 2.06-2.11 (1H, m), 2.21-2.30 (2H, m), 2.55-2.75 (7H,m), 4.06-4.22 (4H, m), 4.80 (2H, s), 6.88 (2H, d), 7.51 (2H, d)

EXAMPLE 2

Ethanol (38 ml), 0.90 g of Hydroxylamine hydrochloride, and 1.64 g oftriethylamine were added to 3.0 g of ethyl4-[4-(4-cyanophenyl)-3-oxo-1-piperazinyl]-1-piperidineacetate, and themixture was heated under reflux for 3 hours. The crystals formed werecollected by filtration at the temperature of about 30° C, andrecrystallized from chloroform-ethanol to give 2.27 g of ethyl4-[4-(4-hydroxyamidinophenyl)-3-oxo-1-piperazinyl]-1-piperidineacetate

Elemental analysis (for C₂₀ H₂₉ N₅ O₄) C (%) H (%) N (%) Calcd. 59.547.24 17.36 Found 59.31 7.05 17.32

NMR spectrum (DMSO-d₆, TMS internal standard): δ: 1.19 (3H, t),1.39-1.48 (2H, m), 1.77-1.80 (2H, m), 2.16-2.21 (2H, m), 2.24-2.27 (1H,m), 2.83-2.89 (4H, m), 3.19 (2H, s), 3.28 (2H, s), 3.62-3.65 (2H, m),4.08 (2H, q), 5.81 (2H, s), 7.34 (2H, d), 7.67 (2H, d), 9.64 (1H, s)

In the same manner as in Example 1, the compound of the followingExample 3 was obtained.

EXAMPLE 3

Methyl4-[4-(4-hydroxyamidinophenyl)-3-oxo-1-piperazinyl]-1-piperidineacetate

Starting compound: Methyl4-[4-(4-cyanophenyl)-3-oxo-1-piperazinyl]-1-piperidineacetate

Elemental analysis (for C₁₉ H₂₇ N₅ O₄ ·0.25 H₂ O) C (%) H (%) N (%)Calcd. 56.63 7.13 17.38 Found. 56.81 6.79 17.26

NMR spectrum (CDCl₃, TMS internal standard): δ: 1.73-1.86 (4H, m),2.22-2.28 (2H, m), 2.34-2.41 (1H, m), 2.87-2.89 (2H, m), 3.02-3.05 (2H,m), 3.25 (2H, s), 3.45 (2H, s), 3.62-3.65 (2H, m), 3.73 (3H, s), 4.83(2H, brs), 7.32 (2H, d), 7.62 (2H, d)

EXAMPLE 4

(±)-cis-Diethyl4-[4-(4-hydroxyamidinophenyl)-1-piperazinyl]-1,3-piperidinediacetate(1.5 g) was dissolved in 50 ml of 1N hydrochloric acid and the solutionwas refluxed overnight. The reaction liquid was concentrated and theconcentrate was purified by ODS column chromatography (eluent: water towater:methanol=1:1) to give 100 mg of(±)-cis-4-[4-(4-hydroxyamidinophenyl)-1-piperazinyl]-1-[(ethoxycarbonyl)methyl]piperidine-3-aceticacid trihydrochloride.

Mass spectrum (mtz): FAB (Pos.) 448 (M⁺ +1)

NMR spectrum (DMSO-d₆, TMS internal standard): δ: 1.18 (3H, t), 1.76(1H, m), 1.98-2.01 (1H.sub., m), 2.10-2.19 (2H, m), 4.06 (2H, q), 5.62(2H, s), 6.89 (2H, d), 7.51 (2H, d), 9.33 (1H, s)

EXAMPLE 5

(±)-cis-Diethyl4-[4-(4-hydroxyamidinophenyl)-1-piperazinyl]-1,3-piperidinediacetate(1.5 g) was dissolved in 50 ml of 1N hydrochloric acid and the solutionwas refluxed overnight. The reaction liquid was concentrated and theconcentrate was purified by ODS column chromatography (eluent: water) togive 450 mg of(±)-cis-4-[4-(4-hydroxyamidinophenyl)-1,3-piperidinediacetic acidtrihydrochloride.

Mass spectrum (m/z): FAB (Pos.) 420 (M⁺ +1)

NMR spectrum (DMSO-d₆, TMS internal standard): δ: 7.15 (2H, d), 7.71(2H, d), 11.09 (1H, s)

EXAMPLE 6

(±)-cis-Diethyl4-[4-(4-amidinophenyl)-1-piperazinyl]-1,3-piperidinediacetatehydrochloride (1.5 g) was dissolved in 150 ml of methylene chloride, 300mg of methyl chloroformate and 30 ml of a 0.2N aqueous sodium hydroxidesolution were added, and the mixture was stirred at room temperature for1 hour. The organic layer was separated, washed twice with water, driedover sodium sulfate, and then concentrated. The resulting residue waspurified by silica gel column chromatography (eluent:chloroform:methanol=50:1) to give 850 mg of (±)-cis-diethyl4-[4-(4-methoxycarbonylamidinophenyl)-1-piperadinyl]-1,3-piperidinediacetate.

Mass spectrum (m/z): FAB (Pos.) 518 (M⁺ +1)

NMR spectrum (CDCl₃, TMS internal standard): δ: 1.24-1.28 (6H, m),1.47-1.59 (3H, m), 1.77 (1H, d), 2.06-2.11 (1H, m), 2.21-2.30 (2H, d),2.54-2.60 (3H, m), 2.63-2.71 (4H, m), 2.88-2.95 (2H, m), 3.17 (2H, q),3.28 (4H, t), 3.78 (3H, s), 4.06-4.19 (4H, m), 6.87 (2H, d), 7.81 (2H,d)

In the same manner as in Example 6, the compound of the followingExample 7 were obtained.

EXAMPLE 7

Ethyl4-[4-(4-methoxycarbonylamidinophenyl)-3-oxo-1-piperazinyl]-1-piperidineacetate

Starting compound: Ethyl4-(4-(4-amidinophenyl)-3-oxo-1-piperazinyl]-1-piperidineacetate

    ______________________________________                                        Elemental analysis (for C.sub.22 H.sub.31 N.sub.5 O.sub.5)                             C (%)         H (%)   N (%)                                          ______________________________________                                        Calcd.   59.31         7.01    15.72                                            Found 59.02 7.03 15.63                                                      ______________________________________                                    

NMR spectrum (CDCl₃, TMS internal standard): δ: 1.28 (3H, t), 1.63-1.75(2H, m), 1.83-1.86 (2H, m), 2.22-2.28 (2H, m), 2.33-2.41 (1H, m),2.90-2.92 (2H, m), 3.01-3.04 (2H, m), 3.23 (2H, s), 3.45 (2H, s),3.69-3.72 (2H, m), 3.78 (3H, s), 4.19 (2H, q), 7.40 (2H, d), 7.90 (2H,d)

EXAMPLE 8

Ethyl4-[4-(4-hydroxyamidinophenyl)-3-oxo-1-piperazinyl]-1-piperidineacetate(0.8 g) was dissolved in 8 ml of water, and 0.21 g of lithium hydroxidemonohydrate was added with ice-cooling. The mixture was stirred for 30minutes with ice-cooling, an aqueous saturated ammonium chloridesolution was added, and the mixture was concentrated. The crystalsformed were collected by filtration to give 0.67 g of4-[4-(4-hydroxyamidinophenyl)-3-oxo-1-piperazinyl]-1-piperidineaceticacid.

    ______________________________________                                        Elemental analysis (for C.sub.18 H.sub.25 N.sub.5 O.sub.4.H.sub.2 O)                   C (%)         H (%)   N (%)                                          ______________________________________                                        Calcd.   54.95         6.92    17.80                                            Found 55.14 6.66 18.00                                                      ______________________________________                                    

NMR spectrum (DMSO-d₆ +CF₃ COOD, TMS internal standard): δ: 2.11-2.14(2H, m), 2.38 (2H, m), 3.17 (2H, m), 3.64-3.77 (5H, m), 4.04-4.07 (2H,m), 4.18 (4H, m), 7.65 (2H, d), 7.83 (2H, d)

In the same manner as in Example 6, the compounds of the followingExamples 9 to 10 were obtained.

EXAMPLE 9

Methyl4-[4-(4-methoxycarbonylamidinophenyl)-3-oxo-1-piperazinyl]-1-piperidineacetate

Starting compound: Methyl4-[4-(4-amidinophenyl)-3-oxo-1-piperazinyl]-1-piperidineacetatehydrochloride

    ______________________________________                                        Elemental analysis (for C.sub.21 H.sub.29 N.sub.5 O.sub.5.0.25 H.sub.2 O)              C (%)         H (%)   N (%)                                          ______________________________________                                        Calcd.   57.85         6.82    16.06                                            Found 57.70 6.60 16.20                                                      ______________________________________                                    

NMR spectrum (CDCl₃, TMS internal standard): δ: 1.63-1.73 (2H, m),1.83-1.86 (2H, m), 2.22-2.28 (2H, m), 2.34-2.40 (1H, m), 2.89-2.92 (2H,m), 3.00-3.03 (2H, m), 3.24 (2H, s), 3.45 (2H, s), 3.70-3.72 (2H, m),3.73 (3H, s), 3.78 (3H, s), 7.40 (2H, d), 7.90 (2H, d)

EXAMPLE 10

Ethyl4-[4-(4-ethoxycarbonylamidinophenyl)-3-oxo-1-piperazinyl]-1-piperidineacetate

Starting compound: Ethyl4-[4-(4-amidinophenyl)-3-oxo-1-piperazinyl]-1-piperidineacetatehydrochloride

    ______________________________________                                        Elemental analysis (for C.sub.23 H.sub.33 N.sub.5 O.sub.5.0.25 H.sub.2 O)              C (%)         H (%)   N (%)                                          ______________________________________                                        Calcd.   59.53         7.28    15.09                                            Found 59.61 7.13 15.08                                                      ______________________________________                                    

NMR spectrum (CDCl₃, TMS internal standard): δ: 1.28 (3H, t), 1.35 (3H,t), 1.63-1.73 (2H, m), 1.83-1.86 (2H, m), 2.23-2.28 (2H, m), 2.34-2.40(1H, m), 2.90-2.92 (2H, m), 3.01-3.04 (2H, m), 3.23 (2H, s), 3.45 (2H,s), 3.70-3.73 (2H, m), 4.17-4.25 (4H, m), 7.43 (2H, d), 7.91 (2H, d)

The chemical structures of the compounds obtained in the Examples aboveare set forth following Table 3 and Table 4.

                                      TABLE 3                                     __________________________________________________________________________      #STR22##                                                                       -                                                                          Ex. No.                                                                           R.sup.1      X.sup.1                                                                          R.sup.2                                                                             X.sup.2                                                                          R.sup.3                                                                             sal.                                       __________________________________________________________________________      1                                                                                                                CHTR23##                                                                    .sub.2 --COOC.sub.2 H.sub.5 CH.sub.2                                          --COOC.sub.2 H.sub.5 --                       - 4                                                                                                             CH.sub.2 --COOC.sub.2 H.sub.5                                               CH.sub.2 --COOH 3HCl                          - 5                                                                                                             CH.sub.2 --COOH CH.sub.2 --COOH 3HCl        - 6                                                                                                             CH.sub.2 --COOC.sub.2 H.sub.5                                               CH.sub.2 --COOC.sub.2 H.sub.5 --           __________________________________________________________________________

                  TABLE 4                                                         ______________________________________                                          #STR27##                                                                      Ex. No.   R.sup.1           X.sup.1                                                                             R.sup.2                                   ______________________________________                                          2                                                                                                               CHTR28##                                                                    .sub.2 --COOC.sub.2 H.sub.5                    - 3                                                                                                            CH.sub.2 --COOCH.sub.3                       - 7                                                                                                            CH.sub.2 --COOC.sub.2 H.sub.5                                                 - 8                                                                           CH.sub.2 --COOH                              - 9                                                                                                            CH.sub.2 --COOCH.sub.3                       - 10                                                                                                           CH.sub.2 --COOC.sub.2 H.sub.5             ______________________________________                                    

In addition to the above-described compounds of examples, othercompounds of the present invention are shown in the following Table 5through Table 9. These compounds can be synthesized, without particularexperiments, in accordance with any one of the above-described inProduction Methods and Processes and modified processes thereof known tothose ordinary skilled in the art.

                                      TABLE 5                                     __________________________________________________________________________      #STR34##                                                                       -                                                                          No.                                                                              R.sup.1 -                                                                  A-                                                                                                       X                                                                             .sup.1 -                                                                           R.sup.2                                       __________________________________________________________________________      1                                                                                                             #STR35##                                                                      #STR36##                                                                    --CH.sub.2 -- --COOC.sub.2 H.sub.5                                              - 2                                                                           #STR37##                                                                      --CH.sub.2 -- --COOC.sub.2 H.sub.5                                            - 3                                                                           #STR39##                                                                      --CH.sub.2 -- --COOC.sub.2 H.sub.5                                            - 4                                                                           #STR41##                                                                      --CH.sub.2 -- --COOC.sub.2 H.sub.5                                            - 5                                                                           #STR43##                                                                      --CH.sub.2 -- --COOC.sub.2 H.sub.5                                            - 6                                                                           #STR45##                                                                      --CH.sub.2 -- --COOC.sub.2 H.sub.5                                            - 7                                                                           #STR47##                                                                      --CH.sub.2 -- --COOC.sub.2 H.sub.5                                            - 8                                                                           #STR49##                                                                      --CH.sub.2 -- --COOC.sub.2 H.sub.5                                            - 9                                                                           #STR51##                                                                      --CH.sub.2 -- --COOC.sub.2 H.sub.5                                            - 10                                                                          #STR53##                                                                      --CH.sub.2 -- --COOC.sub.2 H.sub.5          __________________________________________________________________________

                                      TABLE 6                                     __________________________________________________________________________      #STR55##                                                                       -                                                                          No. R.sup.1 -                                                                 .sup.1 -                                                                                             R.sup.2                                                __________________________________________________________________________      11                                                                                                   #STR56##                                                                    --CH.sub.2 --                                                                   #STR57##                                                - 12                                                                                                --CH.sub.2 --                                                                 #STR59##                                                - 13                                                                                                --CH.sub.2 --                                                                 #STR61##                                                - 14                                                                                                --CH.sub.2 --                                                                 #STR63##                                                - 15                                                                                                --CH.sub.2 --                                                                 #STR65##                                                - 16                                                                                                --CH.sub.2 --                                                                 #STR67##                                                - 17                                                                                                --CH.sub.2 --                                                                 #STR69##                                                - 18                                                                                                --CH.sub.2 --                                                                 #STR71##                                                - 19                                                                                                --CH.sub.2 --                                                                 #STR73##                                                - 20                                                                                                --CH.sub.2 --                                                                 #STR75##                                                - 21                                                                                                --CH.sub.2 --                                                                 #STR77##                                                - 22                                                                                                --CH.sub.2 --                                                                ##STR79##                                             __________________________________________________________________________

                                      TABLE 7                                     __________________________________________________________________________      #STR80##                                                                    No. R.sup.1 -                                                                 .sup.1 -                                                                                         R.sup.2                                                    __________________________________________________________________________      23                                                                                               #STR81##                                                                    --CH.sub.2 --                                                                   #STR82##                                                    - 24                                                                                            --CH.sub.2 --                                                                 #STR84##                                                    - 25                                                                                            --CH.sub.2 --                                                                 #STR86##                                                    - 26                                                                                            --CH.sub.2 --                                                                 #STR88##                                                    - 27                                                                                            --CH.sub.2 --                                                                 #STR90##                                                    - 28                                                                                            --CH.sub.2 --                                                                 #STR92##                                                    - 29                                                                                            --CH.sub.2 --                                                                 #STR94##                                                    - 30                                                                                            --CH.sub.2 --                                                                 #STR96##                                                    - 31                                                                                            --CH.sub.2 --                                                                 #STR98##                                                    - 32                                                                                            --CH.sub.2 --                                                                 #STR100##                                                   - 33                                                                                            --CH.sub.2 --                                                                ##STR102##                                                __________________________________________________________________________

                                      TABLE 8                                     __________________________________________________________________________      #STR103##                                                                   No.                                                                              R.sup.1 -                                                                  .sup.1 -                                                                                           R.sup.2                                                  __________________________________________________________________________      34                                                                                                 #STR104##                                                                   --CH.sub.2 --                                                                   #STR105##                                                 - 35                                                                                              --CH.sub.2 --                                                                 #STR107##                                                 - 36                                                                                              --CH.sub.2 --                                                                 #STR109##                                                 - 37                                                                                              --CH.sub.2 --                                                                 #STR111##                                                 - 38                                                                                              --CH.sub.2 -- --COOC.sub.2 H.sub.5                        - 39                                                                                              --CH.sub.2 -- --COOCH.sub.3                               - 40                                                                                              --CH.sub.2 -- --COOH                                      - 41                                                                                              --CH.sub.2 -- --COOC.sub.2 H.sub.5                        - 42                                                                                              --CH.sub.2 -- --COOCH.sub.3                               - 43                                                                                              --CH.sub.2 -- --COOH                                      - 44                                                                                              --(CH.sub.2).sub.2 -- --COOC.sub.2 H.sub.5                                    - 45                                                                          #STR119##                                                                     --COOC.sub.2 H.sub.5                                   __________________________________________________________________________

                                      TABLE 9                                     __________________________________________________________________________      #STR121##                                                                      -                                                                          No.                                                                              R.sup.1 -                                                                  .sup.1 -                                                                                           R.sup.2                                                                             X.sup.2 -                                                                           R.sup.3                                      __________________________________________________________________________      46                                                                                                             #STR122##                                                                   --CH.sub.2 -- --COOC.sub.2 H.sub.5                                            --CH.sub.2 -- --COOCH.sub.3                     - 47                                                                                                          --CH.sub.2 -- --COOC.sub.2 H.sub.5                                          --(CH.sub.2).sub.2 -- --COOC.sub.2                                            H.sub.5                                         - 48                                                                                                          --CH.sub.2 -- --COOCH.sub.3 --CH.sub.2                                      -- --COOCH.sub.3                                - 49                                                                                                          --CH.sub.2 -- --COOC.sub.2 H.sub.5                                          --CH.sub.2 -- --COOC.sub.2 H.sub.5                                              - 50                                                                          --CH.sub.2 -- --COOC.sub.2 H.sub.5                                          --CH.sub.2 -- --COOCH.sub.3                  __________________________________________________________________________

BRIEF DESCRIPTION OF DRAWING

FIG. 1 represents plasma concentration-time profile of Compound A afteroral administration of compound of Example 2 and Compound A to beagledogs at a dose of 10 mg/kg (mean of three animals standard deriation)

We claim:
 1. A substituted-amidinobenzene derivative of the followinggeneral formula (I) or a salt thereof: ##STR127## wherein the symbols inthe above formula have the following meanings: R¹ : a group which can beconverted into an amidino group in vivo;R² and R³ : the same ordifferent and each represents a carboxyl group or a group which can beconverted into a carboxyl group in vivo; X¹ and X² : the same ordifferent and each represents a lower alkylene group; m: 0, 1 or 2; n: 0or 1, provided that n=1 when m=0.
 2. The substituted-amidinobenzenederivative or a salt thereof as claimed in claim 1, wherein at least oneof R² and R³ is a group which can be converted into a carboxyl group invivo.
 3. The substituted-amidinobenzene derivative or a salt thereof asclaimed in claim 1, wherein the group which can be converted into anamidino group in vivo of R¹ is a group selected from the groupconsisting of a hydroxyamidino group, a lower alkoxycarbonylamidinogroup, a lower alkoxyamidino group and a lower alkanoylamidino group. 4.The substituted-amidinobenzene derivative or a salt thereof as claimedin claim 1, wherein the group which can be converted into an carboxylgroup in vivo of R² and R³ is a group selected from the group consistingof a lower alkoxycarbonyl group, a lower alkoxy-lower alkoxycarbonylgroup, a lower alkoxy-lower alkoxy-lower alkoxycarbonyl group, ahalogeno-lower alkoxylcarbonyl group, a lower alkenyloxycarbonyl group,a lower alkanoyloxy-lower alkoxycarbonyl group, a loweralkenoyloxy-lower alkoxycarbonyl group, a lower alkanoyl-loweralkoxycarbonyl group, a lower alkenoyl-lower alkoxycarbonyl group, alower alkoxy-lower alkanoyloxy-lower alkoxycarbonyl group, a loweralkoxycarbonyloxy-lower alkoxycarbonyl group, a lower alkoxy-loweralkoxycarbonyloxy-lower alkoxycarbonyl group, di-lower alkylamino-loweralkoxycarbonyl group, a cycloalkyloxycarbonyloxy-lower alkoxycarbonylgroup, a lower alkoxybenzyloxycarbonyl group, a nitrobenzyloxycarbonylgroup, a lower alkoxybenzhydryloxycarbonyl group, abenzhydryloxycarbonyl group, a benzoyloxy-lower alkoxycarbonyl group, a2-oxotetrahydrofuran-5-yloxycarbonyl group, a2-oxo-5-alkyl-1,3-dioxolen-4-ylmethoxycarbonyl group, atetrahydrofuranylcarbonyloxymethoxycarbonyl group, and a3-phthalidyloxycarbonl group.
 5. The substituted-amidinobenzenederivative or a salt thereof as claimed in any one of claims 1 to 4,wherein m=1.
 6. The substituted-amidinobenzene derivative or a saltthereof as claimed in claim 1, which is ethyl4-[4-(4-hydroxylamidinophenyl)-3-oxo-1-piperazinyl]-1-piperidineacetate,methyl4-[4-(4-hydroxylamidinophenyl)-3-oxo-1-piperazinyl]-1-piperidineacetate,ethyl4-[4-(4-methoxycarbonylamidinophenyl)-3-oxo-1-piperazinyl]-1-piperidineacetate,methyl4-[4-(4-methoxycarbonylamidinophenyl)-3-oxo-1-piperazinyl]-1-piperidineacetate,ethyl4-[4-(4-ethoxycarbonylamidinophenyl)-3-oxo-1-piperazinyl]-1-piperidineacetate.7. The substituted-amidinobenzene derivative or a salt thereof asclaimed in claim 1, which is ethyl4-[4-(4-hydroxylamidinophenyl)-3-oxo-1-piperazinyl]-1-piperidineacetate.8. A pharmaceutical composition comprising an substituted-amidinobenzenederivative of the following general formula (I) or a salt thereof, and apharmaceutically acceptable carrier: ##STR128## wherein the symbols inthe above formula have the following meanings: R¹ : a group which can beconverted into an amidino group in vivo;R² and R³ : the same ordifferent and each represents a carboxyl group or a group which can beconverted into a carboxyl group in vivo; X¹ and X² : the same ordifferent and each represents a lower alkylene group; m: 0, 1 or 2; n: 0or 1, provided that n=1 when m=0.
 9. The pharmaceutical composition asclaimed in claim 8, which is a GPIIb/IIIa receptor antagonist.
 10. Thepharmaceutical composition as claimed in claim 9, which is a plateletaggregation inhibitor.